The HIV-1 integrase is one three enzymes of HIV and is essential for integration of the viral DNA into the host chromosome, a step required for the continued expression of new virus. It has no human counterpart and is therefore an attractive target for drug design. However, despite the enormous successes with the reverse transcriptase and with the protease inhibitors, there are still no inhibitors of integrase that qualify as therapeutic agents. Now, however, many potential lead compounds exist and are being investigated. We have been able to bind an inhibitor to the active site of the enzyme. This inhibitor binds centrally in the site and provides a new lead compound for antiviral drug design. During the last year we have attempted to crystallize two constructs of integrase, full length and core plus C-terminal domain, bound to various DNA substrates. The integrase carries out two reactions during the integration process, 3' end processing and strand transfer. The molecule can also carry out a third reaction which is essentially the reverse of strand transfer and is known as the disintegration reaction. We have attempted to interact these two integrase constructs with a variety of oligonucleotides representing the U5 end of viral DNA, as well as with various disintegration substrates. For the latter, the length of both the U5 arm and target arms were varied. Having obtained no single diffracting crystals to date, we are now extending the range of variable in this investigation. The goal is find a mutation or combination of mutations which will yield single crystals of either the full length protein or any construct of integrase bound to DNA. We are also continuing our efforts to crystallize the catalytic core domain with various active site inhibitors. Large quantities of the core domain have been obtained by expression in E. coli, and crystals at both pH 7.0 (the original condition) and 5.6 have been obtained. We are currently soaking these crystals with inhibitors as well as cocrystallizing the protein with the inhibitors.